Breast cancer (BC) is the most common malignancy that causes death in women. Global gene-expression profile studies have classified breast cancers into different subtypes, among which, the subtypes lacking expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) are clustered as triple negative BC (TNBC:ER−/PR−/HER2−). Hormone or targeted therapies are not usually effective against TNBC, but systemic treatment, such as anthracycline or taxane-based conventional chemotherapy, demonstrates strong therapeutic efficacy (Rouzier et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clinical cancer research: an official journal of the American Association for Cancer Research 11, 5678-5685, 2005; Carey et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clinical cancer research: an official journal of the American Association for Cancer Research 13, 2329-2334, 2007). However, TNBC patients often present with distant metastases and have poor prognosis. The main cause of chemotherapeutic agent failure is the development of multidrug-resistant (MDR) cancer cells under standard chemotherapeutic regimens; in addition, such regimens damage healthy cells, causing adverse side-effects. Use of non-cross-resistant drugs or biological agents in combination with chemotherapeutic drugs is a possible option for TNBC patients with metastases. However, the prognosis of metastatic TNBC patients remains poor even though such options improve the outcome.
Several studies have indicated that some metastatic cancer cells that respond poorly to treatment possess negatively-charged phosphatidylserine (PS) or anionic structures on their outer membrane, in contrast to healthy cells that are normally zwitterionic. This characteristic allows some selective cytotoxic agents, such as cationic antimicrobial peptides (CAPs), to attack cancers through electrostatic interactions (Hallock et al., Membrane composition determines pardaxin's mechanism of lipid bilayer disruption. Biophysical journal 83, 1004-1013, 2002; Gottler & Ramamoorthy, Structure, membrane orientation, mechanism, and function of pexiganan—a highly potent antimicrobial peptide designed from magainin. Biochimica et biophysica acta 1788, 1680-1686, 2009; and Ramamoorthy et al., Cholesterol reduces pardaxin's dynamics—a barrel-stave mechanism of membrane disruption investigated by solid-state NMR. Biochimica et biophysica acta 1798, 223-227, 2010). Cationic antimicrobial peptides (CAPs) are evolutionarily conserved components of the innate immune system, integral for activity against a broad range of pathogens (Zasloff, Antimicrobial peptides of multicellular organisms. Nature 415, 389-395, 2002; and Zanetti, Cathelicidins, multifunctional peptides of the innate immunity. Journal of leukocyte biology 75, 39-48, 2004). The defensive capabilities of CAPs arise from their structures, which allow them to penetrate anionic bacterial membrane (Powers J P, Hancock R E. The relationship between peptide structure and antibacterial activity. Peptides 24, 1681-1691, 2003). In addition to their antibacterial activities, some CAPs are cytotoxic to certain cancer types, but are less toxic to normal cells (Papo et al., A novel lytic peptide composed of DL-amino acids selectively kills cancer cells in culture and in mice. The Journal of biological chemistry 278, 21018-21023, 2003; Hoskin & Ramamoorthy, Studies on anticancer activities of antimicrobial peptides. Biochimica et biophysica acta 1778, 357-375, 2008; and Ting et al., The mechanisms by which pardaxin, a natural cationic antimicrobial peptide, targets the endoplasmic reticulum and induces c-FOS. Biomaterials 35, 3627-3640, 2014). Treatment of cancer cells with large amounts of CAPs leads to transient membrane lysis (Hilchie et al., Pleurocidin-family cationic antimicrobial peptides are cytolytic for breast carcinoma cells and prevent growth of tumor xenografts. Breast cancer research: BCR 13, R102, 2011; Papo et al., Suppression of human prostate tumor growth in mice by a cytolytic D-, L-amino Acid Peptide: membrane lysis, increased necrosis, and inhibition of prostate-specific antigen secretion. Cancer research 64, 5779-5786, 2004; Rodrigues et al. Effective topical treatment of subcutaneous murine B16F10-Nex2 melanoma by the antimicrobial peptide gomesin. Neoplasia 10, 61-68, 2008; Chen et al., A fish antimicrobial peptide, tilapia hepcidin TH2-3, shows potent antitumor activity against human fibrosarcoma cells. Peptides 30, 1636-1642, 2009; Lin et al., Epinecidin-1, an antimicrobial peptide from fish (Epinephelus coioides) which has an antitumor effect like lytic peptides in human fibrosarcoma cells. Peptides 30, 283-290, 2009; Gaspar et al., Anticancer peptide SVS-1: efficacy precedes membrane neutralization. Biochemistry 51, 6263-6265, 2012; Wang et al., Antitumor effects and cell selectivity of temporin-1CEa, an antimicrobial peptide from the skin secretions of the Chinese brown frog (Rana chensinensis). Biochimie 94, 434-441, 2012). However, low concentrations of CAPs can trigger apoptosis (Kawamoto et al., A novel transferrin receptor-targeted hybrid peptide disintegrates cancer cell membrane to induce rapid killing of cancer cells. BMC cancer 11, 359 (2011; and Huang & Chen, Proteomic analysis reveals that pardaxin triggers apoptotic signaling pathways in human cervical carcinoma HeLa cells: cross talk among the UPR, c-Jun and ROS. Carcinogenesis 34, 1833-1842, 2013), and/or necrosis of cancer cells (Papo et al.; Leuschner et al., Membrane disrupting lytic peptide conjugates destroy hormone dependent and independent breast cancer cells in vitro and in vivo. Breast cancer research and treatment 78, 17-27, 2003; Leuschner & Hansel, Targeting breast and prostate cancers through their hormone receptors. Biology of reproduction 73, 860-865, 2005; van Zoggel H, et al. Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2. PloS one 7, e44351, 2012). CAPs have been reported to induce several intracellular events, including changes in calcium homeostasis, mitochondrial dysfunction, and induction of activator protein-1 (AP-1) (Hilchie et al.; Ting et al.; Huang & Chen; and Wang et al. Rapid cytotoxicity of antimicrobial peptide tempoprin-1CEa in breast cancer cells through membrane destruction and intracellular calcium mechanism. PloS one 8, e60462. 2013). Calcium signaling appears to be activated early on in response to CAPs-induced stress, and mediates downstream activator protein-1 (AP-1) signaling (Ting et al.). AP-1 members are critical mediators of several pathways; these proteins form a dimer with proteins of the JUN proto-oncogene (c-JUN) family (c-JUN, JUNB, JUND) or FBJ murine osteosarcoma viral oncogene homolog (FOS) family (c-FOS, FOSB, FRA1/2). The dimer composition of AP-1 regulates downstream gene expression in response to cellular stimuli or in different cellular contexts, as well as controlling cell fate decisions (Eferl & Wagner, AP-1: a double-edged sword in tumorigenesis. Nature reviews Cancer 3, 859-868, 2003). FRA1 regulates tumor cell growth and metastasis through repression of CDH1 in poorly differentiated TNBC cells (Milde-Langosch, et al., The role of the AP-1 transcription factors c-Fos, FosB, Fra-1 and Fra-2 in the invasion process of mammary carcinomas. Breast cancer research and treatment 86, 139-152, 2004; and Zhao et al., Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer. Cancer research 74, 3983-3994, 2014), which lack FOSB expression (Bamberger et al., Expression pattern of the AP-1 family in breast cancer: association of fosB expression with a well-differentiated, receptor-positive tumor phenotype. International journal of cancer Journal international du cancer 84, 533-538, 1999; and Milde-Langosch et al., FosB is highly expressed in normal mammary epithelia, but down-regulated in poorly differentiated breast carcinomas. Breast cancer research and treatment 77, 265-275, 2003). However, little is known about the role of FOSB in TNBC.
It is still desirable to develop a new therapy for cancer through other targets.